Seeking information about assistive technology: Exploring current practices, challenges, and the need for smarter systems

Ninety percent of the 1.2 billion people who need assistive technology (AT) do not have access. Information seeking practices directly impact the ability of AT producers, procurers, and providers (AT professionals) to match a user's needs with appropriate AT, yet the AT marketplace is interdisciplinary and fragmented, complicating information seeking. We explored common limitations experienced by AT professionals when searching information to develop solutions for a diversity of users with multi-faceted needs. Through Template Analysis of 22 expert interviews, we find current search engines do not yield the necessary information, or appropriately tailor search results, impacting individuals’ awareness of products and subsequently their availability and the overall effectiveness of AT provision. We present value-based design implications to improve functionality of future AT-information seeking platforms, through incorporating smarter systems to support decision-making and need-matching whilst ensuring ethical standards for disability fairness remain

Dynamic phosphoregulation of the cortical actin cytoskeleton and endocytic machinery revealed by real-time chemical genetic analysis

We used chemical genetics to control the activity of budding yeast Prk1p, which is a protein kinase that is related to mammalian GAK and AAK1, and which targets several actin regulatory proteins implicated in endocytosis. In vivo Prk1p inhibition blocked pheromone receptor endocytosis, and caused cortical actin patches to rapidly aggregate into large clumps that contained Abp1p, Sla2p, Pan1p, Sla1p, and Ent1p. Clump formation depended on Arp2p, suggesting that this phenotype might result from unregulated Arp2/3-stimulated actin assembly. Electron microscopy/immunoelectron microscopy analysis and tracking of the endocytic membrane marker FM4-64 revealed vesicles of likely endocytic origin within the actin clumps. Upon inhibitor washout, the actin clumps rapidly disassembled, and properly polarized actin patches reappeared. Our results suggest that actin clumps result from blockage at a normally transient step during which actin assembly is stimulated by endocytic proteins. Thus, we revealed tight phosphoregulation of an intrinsically dynamic, actin patch–related process, and propose that Prk1p negatively regulates the actin assembly–stimulating activity of endocytic proteins

Maximal oxygen uptake and fatty acid oxidation in athletic older men and women and healthy control

Introduction: Cardiopulmonary and musculoskeletal systems deteriorate through middle and into older age. This has a negative impact on physical capability and energy metabolism. The purpose of the present study was to determine the effects of ageing and exercise on peak rates of oxygen uptake (VO2peak) and fatty acid oxidation (PFO).Methods: All participants provided written, informed consent. Masters Athletes (MA: n=40, aged 37-90) specialised in endurance (n=10) or sprint running (n=30) were recruited during the 2012 European MA Championships in Zittau, Germany. Untrained (n=42, aged 18-67; 23 men and 16 women) were recruited from the general Manchester population (UK). The untrained participants also completed 12 weeks very high intensity sprint cycle training (4* 20s at 170% VO2max, 3/wk). VO2max and PFO were assessed using indirect calorimetry and incremental cycle ergometry. Statistical significance was gained by independent samples t-tests using IBM SPSS v.20.Results: The endurance and sprint trained MA were a similar age and had similar VO2max (Endurance MA: 47.22 ml/kg/min (±4.15) vs Sprint MA: 43.52 ml/kg/min (±2.21) p=0.416). Both MA groups were significantly higher than untrained people (38.86 ml/kg/min). MA sprinters and endurance runners had a VO2max similar to 19 years younger untrained, healthy people. Regression analysis showed that VO2max decreased by around 11% per decade after the age of 40 yrs in the MA group and 5% per decade after the age of 40 yrs in the untrained group. PFO was similar in endurance and sprint trained MA (Endurance: 8.09 mg/kg/min (±0.95) vs Sprint: 6.91 mg/kg/min (±0.53) p=0.284). In the untrained group, PFO was significantly lower than MA (p=0.006). Regression showed that PFO of MAs was similar to that of an untrained, healthy person 19 years younger. The sprint-training programme caused VO2max to increase by 10% (Pre: 38.86 ml/kg/min (±1.31) vs Post: 42.84 ml/kg/min (±1.24) p<0.001) and PFO to increase by 18% (Pre: 5.57 mg/kg/min (±0.33) vs Post: 6.58 mg/kg/min (±0.41) p=0.050).Conclusion: These results show that MAs have a cardiopulmonary and metabolic fitness at levels equivalent to someone almost 20 yrs younger. Previously untrained middle-aged people can achieve substantial gains in fitness by completing relatively short duration, but high intensity sprint training and reach levels similar to those observed in the master athletes

Allosteric modulation of AURKA kinase activity by a small-molecule inhibitor of its protein-protein interaction with TPX2.

The essential mitotic kinase Aurora A (AURKA) is controlled during cell cycle progression via two distinct mechanisms. Following activation loop autophosphorylation early in mitosis when it localizes to centrosomes, AURKA is allosterically activated on the mitotic spindle via binding to the microtubule-associated protein, TPX2. Here, we report the discovery of AurkinA, a novel chemical inhibitor of the AURKA-TPX2 interaction, which acts via an unexpected structural mechanism to inhibit AURKA activity and mitotic localization. In crystal structures, AurkinA binds to a hydrophobic pocket (the 'Y pocket') that normally accommodates a conserved Tyr-Ser-Tyr motif from TPX2, blocking the AURKA-TPX2 interaction. AurkinA binding to the Y- pocket induces structural changes in AURKA that inhibit catalytic activity in vitro and in cells, without affecting ATP binding to the active site, defining a novel mechanism of allosteric inhibition. Consistent with this mechanism, cells exposed to AurkinA mislocalise AURKA from mitotic spindle microtubules. Thus, our findings provide fresh insight into the catalytic mechanism of AURKA, and identify a key structural feature as the target for a new class of dual-mode AURKA inhibitors, with implications for the chemical biology and selective therapeutic targeting of structurally related kinases.We are grateful for the access and support at beamlines i02, i03 and i04-1 at Diamond Light Source at Harwell, UK (proposal MX9007 and MX9537) and at beamline Proxima1 at the SOLEIL Synchrotron, Gif-sur-Yvette, France. We are grateful for access and support from the X-ray and biophysics facilities (Dept. of Biochemistry) and the screening/imaging facility (MRC Cancer Unit). M.J. was supported by a Cancer Research UK studentship held in the labs of DS and ARV, PS and MR by a Wellcome Trust Strategic Award to ARV and MH, and DJH, BH, AJN and GM by grants from the UK Medical Research Council to ARV.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/srep2852

STAT6 and Furin Are Successive Triggers for the Production of TGF-β by T Cells

Production of TGF-β by T cells is key to various aspects of immune homeostasis, with defects in this process causing or aggravating immune-mediated disorders. The molecular mechanisms that lead to TGF-β generation by T cells remain largely unknown. To address this issue, we take advantage of the fact that intestinal helminths stimulate Th2 cells besides triggering TGF-β generation by T lymphocytes and regulate immune-mediated disorders. We show that the Th2 cell-inducing transcription factor STAT6 is necessary and sufficient for the expression of TGF-β propeptide in T cells. STAT6 is also necessary for several helminth-triggered events in mice, such as TGF-β-dependent suppression of alloreactive inflammation in graft-versus-host disease. Besides STAT6, helminth-induced secretion of active TGF-β requires cleavage of propeptide by the endopeptidase furin. Thus, for the immune regulatory pathway necessary for TGF-β production by T cells, our results support a two-step model, composed of STAT6 and furin

A systematic screen for protein–lipid interactions in Saccharomyces cerevisiae

Lipids are important cellular metabolites, with a wide range of structural and functional diversity. Many operate as signaling molecules. Lipids though have rarely been studied in large-scale interaction screen; they are poorly represented in current biological networks.Here, we describe the use of miniaturized lipid–arrays for the large-scale study of protein–lipid interactions. In yeast, we show general feasibility with a systematic screen implying 172 proteins. We report 530 protein–lipid associations, the majority is novel and several were validated using other techniques.The screen uncovers numerous insights into lipid function in yeast and equivalent systems in humans. It revealed (i) previously undetected cryptic lipid-binding domains, (ii) series of new cellular targets for sphingolipids and (iii) new ligands for some PH domains that can cooperatively bind additional lipids and work as coincidence sensor to integrate both phosphatidylinositol phosphates and sphingolipid signaling pathways.The significant number of biological insights uncovered shows that even major classes of metabolites have been insufficiently studied. This illustrates the general relevance of such systematic screens and calls for further system-wide analyses

The Effect of Diet-Induced Obesity and Subsequent Weight Loss on Body Composition, Glucose Clearance, Metabolite Profile and Liver Amp-Activated Protein Kinase in Mice

Obesity, currently an epidemic, is a difficult disease to combat because it is marked by both a change in body weight and an underlying dysregulation in metabolism, making consistent weight loss challenging. We sought to elucidate this metabolic dysregulation resulting from diet-induced obesity (DIO) that persists through subsequent weight loss. We hypothesized that weight gain imparts a change in “metabolic set point” persisting through subsequent weight loss and that this modification may involve a persistent change in hepatic AMP-activated protein kinase (AMPK), a key energy-sensing enzyme in the body. To test these hypotheses, we tracked metabolic perturbations through this period, measuring changes in hepatic AMPK. To further understand the role of AMPK we used AICAR, an AMPK activator, following DIO. Our findings established a more dynamic metabolic model of DIO and subsequent weight loss. We observed hepatic AMPK elevation following weight loss, but AICAR administration without similar dieting was unsuccessful in improving metabolic dysregulation. Our findings provide an approach to modeling DIO and subsequent dieting that can be built upon in future studies and hopefully contribute to more effective long-term treatments of obesity

Differences in Vastus Lateralis muscle thickness and maximum knee extension force between Master athletes, non-athletes and patients undergoing major abdominal surgery

INTRODUCTION: An important cause of frailty in old age is sarcopenia, which is associated with poor prognosis in major abdominal surgery1. While muscle mass is important, there is increasing evidence that the force generating capacity is proportionally more reduced during ageing than muscle mass2. The aim of this study is to obtain a measure of muscle size (Vastus Lateralis (VL) thickness), muscle function (maximal voluntary force generating capacity (MVC)) and the ratio between MVC and VL thickness, providing a measure of ‘muscle quality’. As a substantial component of the development of frailty is likely to be attributable to low levels of physical activity, we hypothesise that 1) muscle mass and function are lower in patients undergoing a major abdominal surgery compared to age-matched Master athletes (MAs) and non-MAs and 2) poor muscle function is predictive of poor surgical outcomes in patients undergoing major abdominal surgery. METHODS: Major abdominal surgery patients (hepatobiliary, MASP) were recruited during a preoperative clinic at MFT (UK). Non-MAs were recruited from the general population of Manchester, presented without any co-morbidities, whilst sprint-trained MAs were recruited from members of Finnish Track and Field Organizations. Ultrasound images of the VL were processed (ImageJ v.1.80) to obtain VL thickness (in mm). A strap placed above the tibial malleolus and attached to a custom dynamometer recorded MVC (in N) during a maximal isometric knee extension while participants were sitting down on a chair with knee and hip at 90°. Surgical outcomes were length of stay in hospital (LOS) (in days) and readmission after surgery. Differences in VL thickness and MVC/VL thickness between groups was assessed with an ANCOVA with age as covariate to assess differences in the age-related decline. Bonferroni post-hoc test assessed differences between groups. RESULTS: A total of 98 male participants were included (MASP: N=31, 73±6 yrs, non-MAs: N=20, 73±5 yrs and MAs: N=47, 71±6 yrs). The mean LOS was 6 days (range: 2-12 days) No significant differences were found in VL thickness between groups (p=0.099), however MVC/VL thickness was lower in MASP compared with MAs and non-MAs (p0.05). In the patient group, no significant relationship was found between VL thickness or MVC/VL thickness with LOS, and no difference was found in VL thickness and MVC/VL thickness between readmitted and non-readmitted patients (p>0.05). CONCLUSION: Muscle quality, but not muscle thickness, appears to be negatively affected in MASP when compared to age matched controls. Future work should explore the impact of muscle quality on long-term surgical outcomes (1-year and 3-year survival rate) as similarly to our previous work, we found no relationship between any muscle parameter and short-term surgical outcomes3. A limitation of this study is that only male was included

Yes, we should! EU priorities for 2019-2024. EPC Challenge Europe Issue 24, April 2019

The European Union (EU) is not alone in its struggle to grapple with the major headaches of our times. The Western world as a whole is affected. Inside the Union, the crises in and of its national societies and democracies have radiated to the EU level. Half of the member states have minority governments. If they are politically weak in their own countries, how can the Union be strong? The EU is, after all, also the sum of its member states

Conceptual Representations for Computational Concept Creation

Computational creativity seeks to understand computational mechanisms that can be characterized as creative. The creation of new concepts is a central challenge for any creative system. In this article, we outline different approaches to computational concept creation and then review conceptual representations relevant to concept creation, and therefore to computational creativity. The conceptual representations are organized in accordance with two important perspectives on the distinctions between them. One distinction is between symbolic, spatial and connectionist representations. The other is between descriptive and procedural representations. Additionally, conceptual representations used in particular creative domains, such as language, music, image and emotion, are reviewed separately. For every representation reviewed, we cover the inference it affords, the computational means of building it, and its application in concept creation.Peer reviewe